Abstract
The aberrant activation of the Gli family of zinc finger transcription factors (ZFTFs) is associated with several types of human cancer, including medulloblastoma and basal cell carcinoma. We have reported the use of cobalt(III) Schiff-base complexes (Co(III)-sb) as potent inhibitors of ZFTFs in vivo. These complexes inhibit transcription by displacing the zinc finger domain‘s structural Zn(II) ion, destabilizing the alpha helix necessary for DNA recognition. Here, we describe the use of Co(III)-sb complexes for the selective inhibition of Gli1. Spectroscopic and computational studies of the Gli1 DNA binding domain found that Co(III)-sb displaced Zn(II) through direct coordination with the His residues of the Cys2His2 Zn(II) binding site. As a result, there is a dose-dependent degradation of the alpha-helix content in the DNA binding domain of Gli1 and corresponding inhibition of consensus sequence recognition. We conclude that this strategy is well suited for the development of new and potent inhibitors of Gli1.
| Original language | English (US) |
|---|---|
| Article number | e202200025 |
| Journal | ChemMedChem |
| Volume | 17 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 20 2022 |
Funding
This work was supported by the US National Institutes of Health (NIH) award R01 GM121518-04. Biophysical measurements were conducted at the Keck Biophysics Facility, a shared resource of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University supported in part by the NCI Cancer Center Support Grant #P30 CA060553. MS and NMR measurements were made at the IMSERC NMR facility at Northwestern University, which received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633) NIH 1S10OD012016-01 / 1S10RR019071-01 A1, and Northwestern University. In addition, peptide synthesis was performed at the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. This facility has current support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633). This work was supported by the US National Institutes of Health (NIH) award R01 GM121518‐04. Biophysical measurements were conducted at the Keck Biophysics Facility, a shared resource of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University supported in part by the NCI Cancer Center Support Grant #P30 CA060553. MS and NMR measurements were made at the IMSERC NMR facility at Northwestern University, which received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS‐2025633) NIH 1S10OD012016‐01 / 1S10RR019071‐01 A1, and Northwestern University. In addition, peptide synthesis was performed at the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. This facility has current support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS‐2025633).
Keywords
- DNA recognition
- cancer
- cobalt
- inhibitors
- molecular dynamics
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine
- Biochemistry
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology
- Organic Chemistry
